CH641458A5 - Process for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid esters - Google Patents

Description

The present invention relates to a process for the preparation of new pyrrole-1-carboxylic acid compounds, namely the (d, l) - and (l) -5-aroyl-l, 2-dihydro-3H-pyrrolo [l, 2- a] -pyrrole-l-carboxylic acid ester of the formula:

COOH

in which R represents the hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, R1 represents the hydrogen atom, an alkyl radical having 1 to 4 carbon atoms, an alkoxy radical having 1 to 4 carbon atoms, the chlorine atom, the fluorine atom or the bromine atom, the substituent R1 being in the is in the o-, m- or p-position of the aroyl group, and R2 represents a Ci-Ct-alkyl radical.

The (d, l) and (l) forms of the compounds of formula XI have anti-inflammatory, analgesic and antipyretic effects and are therefore valuable for the treatment of inflammation, pain and / or pyrexia in mammals and humans, as described in detail below becomes. They are also excellent muscle relaxants.

Typical C 1 -C 4 -alkyl esters are, for example, the methyl, ethyl, propyl, isopropyl, butyl and tert-butyl esters.

The new compounds of formula XI as disclosed below exist in the form of optical isomers or enantiomorphs, i.e. in the form of (d, l) mixtures. The (l) compound as well as the (d, l) mixtures are encompassed by the present invention.

Should the new compounds because of their pharmacological properties, e.g. their anti-inflammatory, analgesic or antipyretic effect, i.e. used as medicaments, a preferred subgroup will be found among the (l) -carboxylic acid esters of the formula XI.

Another subgroup of compounds to be used as medicaments are the compounds of the formula XI and the (l) -carboxylic acid esters of the formula XI, in which R and R1 each represent hydrogen atoms.

The (d) carboxylic acid esters of formula XI are valuable as intermediates for the preparation of (d, l) carboxylic acids of formula A, as will be described in more detail below.

According to the invention, the compounds of the formula XI are prepared by the process defined in claim 1. This process and the preparation of the starting products can be represented according to the following reaction scheme:

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COOH

(A)

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4th

wherein R and R1 have the above meanings and R2 e.g. means the methyl, ethyl, isopropyl or n-butyl radical.

In practice, one will advantageously convert equimolecular amounts of ethanolamine of formula I and dimethyl 1,3-acetonedicarboxylate of formula II at a temperature of 0 ° C to room temperature for the preparation of the compound of formula IV, in which R represents the hydrogen atom, to in this way to easily reach a solution of the vinylamine of the formula III, which is then preferably in situ in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at a temperature of 40 ° C. to 100 ° C treated for 30 minutes to 16 hours. Suitable solvents for this reaction are aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane, etc. In the preferred embodiments, the reaction in acetonitrile solution takes place at reflux temperature for about 1 hour. The compounds used as reactants, i.e. 2-bromoacetaldehyde and 2-chloroacetaldehyde are known compounds. They can be obtained by pyrolysis of the corresponding diethylacetals in the presence of oxalic acid dihydrate.

In order to obtain the compounds of the formula IV in which R is a lower, preferably straight-chain alkyl radical having 1 to 4 carbon atoms, an aqueous mixture of ethanolamine of the formula I and 1,3-acetone dicarboxylic acid dimethyl ester of the formula II with a compound of the following formula is expediently used :

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3 11

fr-ocH2x wherein X is bromine or chlorine and R3 is a lower alkyl radical having 1 to 4 carbon atoms, which is preferably a straight-chain radical, treated at 40 to 100 ° C for 30 minutes to 16 hours. Preferred compounds for this are 1-bromoacetone, l-bromo-2-butanone, l-bromo-2-pentanone and l-bromo-2-hexanone. According to a preferred embodiment, the reaction takes place at a temperature of from -10 ° C. to room temperature for 1 hour to 6 hours. The compounds of the formula:

0

r3-c-ch2x are known.

By esterification of a compound of formula IV with methanesulfonyl chloride in the presence of a tertiary amine, e.g. Triethylamine, pyridine or the like, preferably in the presence of a cosolvent such as e.g. Dichloromethane at a temperature in the range from -10 ° C to room temperature for 10 minutes to 2 hours, can be obtained to a corresponding mesylate of formula V, which is then reacted with sodium iodide in acetonitrile solution at reflux temperature for a period of 1 hour to 10 hours is converted into a corresponding N- (2-iodo-ethyl) pyrrole.

By reacting the iodomethyl compounds of the formula VI with sodium hydride in a suitable, inert, organic solvent, e.g. Dimethylformamide, a 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l, 7-dicarboxylic acid dimethyl ester of the formula VII and all-alkyl-substituted derivatives thereof in the 6-position can be obtained. This cyclization takes place in an inert atmosphere, i.e. in an argon or nitrogen atmosphere, at temperatures in the range of

15 ° C to 40 ° C for a period of 15 minutes to 4 hours. The best results are obtained if the reaction is carried out at room temperature for about 30 minutes, provided that the radical R represents the hydrogen atom.

On the other hand, the compounds of formula VII can also be obtained by direct cyclization of a mesylate of formula V using sodium hydride in dimethylformamide solution at a temperature of from -10 ° C. to room temperature for 30 minutes to 2 hours.

The basic hydrolysis of a compound of formula VII with an alkali metal hydroxide or other alkali metal carbonate, e.g. Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous, low aliphatic alcohol, e.g. Methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 hours to about 24 hours results in a free diacid of Formula VIII, i.e. 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylic acid and 6-alkyl derivatives thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for about 10 hours.

The carboxylic acid group at the C-1 position in a compound of formula VIII can then be treated by treatment with a lower aliphatic alcohol, e.g. Methanol, ethanol, isopropanol, n-butanol or the like, are selectively esterified in the presence of hydrogen chloride, using a 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-7-carboxylic acid 1- carboxylic acid alkyl ester of Form IX. The reaction takes place at a temperature between 0 ° C and 50 ° C for 1 hour to 4 hours.

The decarboxylation of the monoesterified compounds of the formula IX to corresponding compounds of the formula X, which are the key intermediates in the process, is advantageously carried out by heating a compound of the formula IX to an elevated temperature of 230 ° C. to 280 ° C. for a sufficiently long period of time to achieve a full implementation. The course of the reaction can be determined on the basis of the extent of the evolution of carbon dioxide and by thin layer chromatography, the decarboxylation generally being completed within 45 to 90 minutes. The reaction products, namely the 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid alkyl esters and the 6-alkyl derivatives thereof, which correspond to the formula X, can be purified by chromatographic methods. On the other hand, especially in the decarboxylation of small amounts of compounds of the formula IX, the reaction product of the formula X can be obtained directly from the reaction vessel by distillation.

The condensation of a compound of formula X with an amide of the following formula:

, O ~ C0N <CH3'2 '

R

where R1 has the above meaning leads to corresponding 5-aroyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carbonic acid alkyl esters of the formula XI. This reaction is preferably carried out in an inert, organic, aprotic solvent and in the presence of phosphorus oxychloride at the reflux temperature for about 1 hour to about 175 hours in an inert atmosphere, followed by refluxing in the presence of sodium acetate for 2 to 10 hours. Instead of phosphorus oxychloride, other acid chlorides, e.g. Use phosgene or oxalyl chloride.

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According to a preferred embodiment, this condensation is carried out by adding a solution of a compound of formula X in a suitable solvent to a mixture of 1.1 to 5 molar equivalents of both the desired amide and the phosphorus oxychloride in the same solvent which has been heated under reflux beforehand, so The reaction mixture obtained is heated to boiling under reflux in an argon atmosphere for 6 to 72 hours, and 3 to 10 molar equivalents of sodium acetate are then added. The mixture is then heated to boiling under reflux for a further 4 to 6 hours.

Adequate solvents for this reaction are halogenated hydrocarbons, e.g. Dichloromethane, 1,2-dichloroethane, chlorofom, carbon tetrachloride etc., also dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Examples of suitable N, N-dimethylarylamides that can be used are:

N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl N, N -Dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl -N, N-dimethyl-

• benzamide,

O-toluamide,

■ m-toluamide,

P-toluamide,

P-ethylbenzamide,

■ o-propyl-benzamide,

M-butyl-benzamide,

o-methoxy-benzamide,

m-methoxy-benzamide,

p-ethoxy-benzamide,

p-isopropoxy-benzamide,

o-chloro-benzamide,

m-chloro-benzamide,

p-chloro-benzamide,

o-fluoro-benzamide,

p-fluoro-benzamide,

m-bromo-benzamide and p-bromo-benzamide.

These amides are known, commercially available compounds. You can in the usual way from the corresponding acids, i.e. by conversion to the acid chlorides and by subsequent treatment with dimethylamine.

Of course, the isolation of the compounds described in the present patent can, if desired, be accomplished using any suitable separation and purification methods such as e.g. Carry out extraction, filtration, evaporation, distillation, allowing to crystallize out, thin-layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or by a combination of these measures. Suitable separation and isolation methods can be found in the examples given below. Of course, you can also use other equivalent separation and isolation methods.

The compounds of formula XI and their (I) isomers are valuable anti-inflammatory agents, analgesic agents, agglutination inhibitors, fibrinolytics and muscle relaxants. These compounds can be used both prophylactically and therapeutically.

The preparations containing these compounds are valuable for the treatment and healing of inflammation, e.g. Inflammation of the skeletal muscles, joints and other tissues, for example in the treatment of inflammations of this type, such as e.g. Rheumatism, concussio, laceratio, arthritis, bone fractures, post-traumatic conditions and gout. In those cases where the above conditions cause pain and fever, coupled with inflammation, the connections to correct these conditions as well as the inflammation are extremely valuable.

The active compounds of the formula XI or their (I) isomers can be administered, for example, orally, parenterally or topically in the form of tablets, suppositories, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments or the like. preferably in unit dosage form.

The preferred mode of administration for the compounds detailed below is oral administration using an appropriate daily dosage amount which is used depending on the degree of the disease. In general, a daily dose of between 25 mg and 500 mg of active substance of formula A or a (/) acid isomer thereof or of pharmaceutically acceptable esters and salts thereof is administered. In most cases, treatment is carried out at a dose of 0.5 mg to 6 mg per kg of body weight per day. For such oral administration, pharmaceutically acceptable, non-toxic preparations will be formed by adding any of the normally used excipients such as e.g. pharmaceutically acceptable mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. Such preparations can be marketed in the form of solutions, suspensions, tablets, pills, capsules, powders, prolonged-release preparations, etc.

The active substances of the formula XI and their (Z) isomers 30 can be processed into a suppository using, for example, polyalkylene glycols, such as polypropylene glycol, as carriers. Liquid, pharmaceutically administrable preparations can be, for example, by dissolving, dispersing, etc. an active substance of the type described above 3s and optionally pharmaceutical excipients in a carrier such as e.g. Water, saline, aqueous dextrose, glycerin, ethanol and the like can be prepared, whereby a solution or suspension is obtained. If desired, the pharmaceutical preparation to be administered can also contain small amounts of non-toxic auxiliary substances, e.g. Wetting or emulsifying agents, pH buffering agents, etc., e.g. Sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. included.

Methods for the preparation of such dosage forms are well known or readily available to the person skilled in the art. In this context, reference is made, for example, to Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 14th edition, 1970. In all cases, the preparation to be administered will contain a certain amount of active substance or active substances in a pharmaceutically effective amount.

The compounds of the formula XI and their (Q isomers are also relaxants for the uterine muscles and are therefore valuable 55 as agents which influence pregnancy both in favor of the mother and / or the fetus until the final stage of pregnancy. It should be noted that in In those cases where labor has already started, which is particularly the case immediately before birth, the administration of the compounds described here cannot prolong the pregnancy indefinitely, in which case the pregnancy is most likely only slightly prolonged », A factor that can be beneficial for the mother and / or the fetus.

In particular, the compounds of formula XI and their (I) isomers can be used as agents for delaying the onset or for postponing labor

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will. The term "delaying the onset of labor" should refer to any point in time before the start of uterine contractions. This expression is thus intended to prevent abortion at the beginning of pregnancy, i.e. before the fetus is viable, as well as delaying premature labor, a term that is sometimes used to refer to premature labor, which experience has shown to occur later in pregnancy, when the fetus is already considered viable. In any case, the agents can be used as prophylactic agents because such administration prevents labor onset. Administration is for the treatment of women with a history of spontaneous bortus, miscarriage or preterm birth, i.e. Delivery before the end of the entire gestation period, particularly valuable. Such administration is also valuable in those cases where there are clinical indications that the pregnancy should end prematurely, so that such administration could be particularly advantageous for the mother and / or the fetus.

As for animals, this treatment can also be used to synchronize the birth of a group of pregnant animals or to control such births at the desired time and / or location where such births can be performed with greater ease.

Here, the term "shifting of contractions" is intended to mean the delay in contractions which is caused by the administration of compounds of the formula XI or their (i) isomers after the onset of uterine muscle contractions. The patient's condition, including the duration within the gestational period in which the contractions started, the extent of the contraction, and the duration of the contractions will affect the results obtained by the administration of the compounds. The effect can be, for example, that the intensity and / or the duration of the contractions (whereby the actual labor contraction becomes “extendable”) can be shortened or the contractions can be interrupted at all. In any case, the gestation period is prolonged, although, depending on the patient's conditions, the effect can either be very weak or, under certain circumstances, somewhat larger. Such administration can prevent spontaneous abortion, make the birth easier and / or less painful for the mother, or can lead to the fact that the birth can be carried out at a more suitable time and / or in a more suitable place.

In general, a daily dose of 0.5 mg to about 25 mg of active ingredient per kg of body weight will be administered, the administration being carried out once a day or in smaller doses regularly three or four times a day.

The following examples illustrate the present invention. The abbreviation t.l.c., if it occurs here, refers to thin layer chromatography, while all mixing ratios with respect to liquids represent volume ratios. Unless otherwise stated, the reaction takes place at room temperature, i.e. at temperatures in the range of 20 to 30 ° C.

Production of the starting products

1. A 250 ml three-necked round bottom flask, which has a magnetic stirrer and is equipped with a drying tube filled with calcium chloride, is directly (via one of the outer openings) with a supply line and a short (3 ") water condenser with the acetal pyroly-

connected device. The latter consists of a 100 ml round-bottomed flask which has previously been treated with 15.6 g oxalic acid dihydrate and 11.82 g bromoacetaldehyde diethyl acetal, made from vinyl acetate as described by P.Z. Bedoukian, J. Am. Chem. Soc. 66, 651 (1944), a 6 "Vigreux column, which has a thermometer, which is connected to the aforementioned condenser, is placed on this device.

The three-necked flask is charged with 3.36 g of ethanolamine, cooled to 0 to 10 ° C. in an ice bath, and treated dropwise with 8.7 g of dimethyl-1,3-acetone dicarboxylate while stirring. This spontaneously forms methyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III). When the addition is complete, the ice bath is removed and 100 ml of dry acetonitrile are added. The pyrolysis part of the device is placed in an oil bath and the temperature of the latter is allowed to rise to 150 to 160 ° C. The bromoacetaldehyde solution formed is distilled directly into the magnetically stirred solution of vinylamine III (boiling point 80 to 83 ° C./580 mm). As soon as the distillation temperature has dropped to less than 80 ° C., the pyrolysis device is interrupted and replaced by a reflux condenser equipped with a drying tube containing calcium chloride. The solution is then heated at reflux temperature for 1 hour, the solvent is removed under reduced pressure and then 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is evaporated to dryness in vacuo and fed to a column coated with 200 g of silica gel, which contains hexane. The column is then eluted with a mixture of hexane and ethyl acetate (mixing ratio 80:20) (500 ml) and a mixture of hexane and ethyl acetate (mixing ratio 1: 1; 9 x 500 ml). Fractions 2 and 3 contain less polar impurity and dimethyl-1,3-acetone dicarboxylate; fractions 4 to 8 yield 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxy-pyrrole-2-acetate (IV, R = H), which after recrystallization from a mixture of ether and hexane has a melting point from 52 to 54 ° C.

2. 2.65 ml of triethylamine are stirred into a solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrroI-2-acetate in 35 ml of dry dichloromethane, cooled to -10 ° C., whereupon 1.46 ml of methanesulfonyl chloride are added dropwise while maintaining a temperature of the reaction mixture of from -10 ° C. to -5 ° C. adds. The course of the reaction is observed by thin layer chromatography analysis using a mixture of chloroform and acetone (mixing ratio 90:10). As soon as the reaction can be regarded as complete (30 minutes after the addition of methanesulfonylchloride has ended), 10 ml of water are slowly added. The organic phase is separated off, washed three times with 30 ml of water each time, dried over sodium sulfate and evaporated to dryness under reduced pressure. Allowing the residue to crystallize out from a mixture of dichloromethane and hexane gives 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R - H ), Mp. 99 to 101 ° C.

3. A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is heated to boiling under reflux for 1 hour. Then the reaction mixture is cooled and then evaporated to dryness under reduced pressure and the residue is triturated with water. The insoluble material is separated off by filtration and air-dried, 840 mg (97%) of methyl-N- (2-

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iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), mp. 137 to 138 ° C.

4. A solution of 1 g of methyl-N- (2-iodoethyl) -3-carbo-methoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred in an argon atmosphere with 137 mg of 50% sodium hydride in mineral oil. Then the reaction mixture is kept at room temperature for 30 minutes and then treated with 100 ml of water. The product is extracted three times with 50 ml of ethyl acetate each time and the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue over 20 g of silica gel using a mixture of hexane and ethyl acetate (mixing ratio 4: 1) as the eluent gives 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a ] -pyrrole-1,7-dicarboxylate (VII, R = H), mp 70-71 ° C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylate in 20 ml of methanol is mixed with a solution of 4.48 g of potassium hydroxide treated in 20 ml of water and the reaction mixture was then heated to boiling under reflux for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted three times with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, giving 1.51 g (95%) 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H), mp. 220 ° C (decomposition).

5. A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l, 7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is maintained with gaseous hydrogen chloride a temperature of the reaction mixture of less than 50 ° C saturated. The ice bath is then removed and the reaction mixture is stirred for 1 Vi hours at room temperature and evaporated to dryness under reduced pressure. Then the residue is mixed with 10 ml of benzene. The solution is then evaporated once more in vacuo, repeating this procedure three times in total to remove the excess hydrogen chloride. In this way, 1.58 g (96%) of isopropy 1-1,2-dihydro-3 H -pyrrolo- [1,2-a] -pyrrole-1-carboxy-lat-7-carboxylic acid (IX, R = H, R2 = ÌC3H7), which has a melting point of 144 to 145 ° C after crystallization from a mixture of methanol and ethyl acetate.

Similarly, when using methanol, ethanol, propanol and n-butanol instead of isopropanol, the following compounds are obtained:

Methyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate-7-carboxylic acid,

Ethyl 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid,

Propyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate-7-carboxylic acid and

Butyl-1,2-dihydro-3 H -pyrrolo- [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid.

6. 1.054g of isopropyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate-7-carboxylic acid are in a dry round-necked flask with a capacity of

10 ml heated to 240 to 250 ° C, the reaction product being distilled off directly from the reaction vessel. In this way, 745 mg (87%) of isopropy 1-1,2-dihydro-

3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate (X, R = H,

R2 = ÌC3H7), pale yellow oil with the following physical

Constants:

U.V .:> ^ ° h215 nm (e = 6020);

I.R.:u.00cll1725cm- ';

NMR: S? Ss'J 1.22 (d, J = 7 Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H), 4.65 -5.2 (m, 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3 Hz, 1H), 6.43-6.53 ppm. (m, 1H).

7. A 100 ml three-necked round bottom flask equipped with a condenser, a nitrogen inlet tube and a gas inlet tube is charged with 5.0 g of isopropyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l- carboxylate-7-carboxylic acid charged. The device is flushed out thoroughly with nitrogen and the nitrogen supply is then stopped. The device is then immersed in an oil bath heated to 270 ° C. and the reaction is observed on the basis of the evolution of carbon dioxide (gas inlet connector) and by thin-layer chromatography on silica gel using a mixture of benzene, dioxane and acetic acid (mixing ratio 90: 10: 1) as developer solvent . The reaction is practically complete after 45 minutes. After 1 hour, the container is removed from the oil bath and the contents of the reaction flask are placed in a round bottom flask which is provided with 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography over 100 g of silica gel. The fractions eluted using a mixture of hexane and benzene (mixing ratio 70:30) and a mixture of hexane and benzene (mixing ratio 50:50) yield 2.77 g (68%) of isopropyl-1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate (X, R = H, R2 = iC3H?), an oil whose physical constants are identical to those according to Example 6.

example 1

A solution of 179 mg N, N-dimethyl-p-toluamide and

0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is heated to boiling under reflux for 30 minutes. A solution of 193 mg of isopropy 1-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate in 2 ml of 1,2-dichloroethane is then added to this solution. The reaction mixture is then refluxed for 8 hours in an argon atmosphere, then treated with 405 mg of sodium acetate and then refluxed for a further 5 hours. The mixture obtained is then evaporated to dryness and the residue is chromatographed over 12 g of silica gel, eluting with a mixture of hexane and ethyl acetate (mixing ratio 3: 1). In this way, 208 mg (66%) of isopropyl-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate (XI, R = H, R1 = p-CH3, R2 = ÌC3H7), an oil with the following physical constants:

U.V .: A.Iex0H 256.312 nm (e = 8700.19500);

1st row: <£ 1735.1620.1605 cm "1;

NMR: SÇgp 1.23 (d, J = 7 Hz, 6H), 2.38 (s, 3H), 2.5-3.0 (m, 2H), 3.75-4.10 (m, 1H) ), 4.2-4.60 (m, 2H), 4.85-5.20 (m, 1H), 5.95 (d, J = 4 Hz, 1H), 6.70 (d, J = 4 Hz, 1H), 7.10 (d, J = 8 Hz, 2H), 7.60 ppm. (d, J = 8 Hz, 2H).

Example 2

When working according to the methods described in sections 6 or 7, the compounds obtained in section 5 can be converted into:

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Methyl 1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1 carboxylate, ethyl 1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole -1-carboxylate, propyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate and

Butyl 1,2-dihydro-3 H-pyrrolo [1,2-a] pyrrole-1 carboxylate.

After the condensation of this compound with N, N-dimethyl-p-toluamide according to the method of Example 1, the following compounds are obtained:

Methyl 5-p-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Ethyl 5-p-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Propyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate and

Butyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1 carboxylate.

Example 3

The procedure according to Example 1 is carried out using 1.1 to 5 molar equivalents:

N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl-N, N-dimethyl N, N-dimethyl -

benzamide,

o-toluamide,

m-toluamide,

p-ethylbenzamide,

o-propyl-benzamide,

m-butyl-benzamide,

o-methoxy-benzamide,

p-methoxy-benzamide,

p-ethoxy-benzamide,

p-isopropoxy-benzamide,

o-chloro-benzamide,

m-chloro-benzamide,

p-chloro-benzamide,

ö-fluoro-benzamide,

P-fluorobenzamide,

m-bromo-benzamide and o-bromo-benzamide

Isopropyl-5-m-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, an oil with the following physical constants:

s U.V .: ^0 "250-251,310-312 nm (s 6460,17400);

I.R.: u.00Ch 1735.1620 cm-1;

NMR: 8 £ 5! H 1.25 [d, 6H, (CH3) 2CH], 2.27 (s, 3H, CHj), 2.52-3.13 (m, 2H, H-2), 3 , 92 (dd, 1H, H-1), 4.13-4.70 (m, 2H, H-3); 4.95 [sept. IH, (CHa ^ H], 5.95 (d, IH, H-7), 6.67 (d, io 1 H, H-6), 7.03-7.57 ppm. (M, 4H; Phenyl protons).

Isopropyl-5-p-ethylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrol-1-carboxylate,

Isopropyl-5-o-propylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -15 pyrrole-1-carboxylate,

Isopropyl-5-m-butylbenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate,

Isopropyl-5-o-methoxybenzoyl-1,2-dihydro-3 H -pyrrolo- [1,2-a] -pyrrole-1-carboxylate, 20 isopropyl-5-p-methoxybenzoyl-l, 2-dihydro-3H -pyrrolo- [1,22-aj-pyrrole-l-carboxylate with the following physical constants:

U.V. ? CxOH 218.270-284 (shoulder), 314 nm (e 9780.9320, 25 22400);

I.R .: i) ™ Ci> 1730.1605 cm- ';

N.M.R .: 1.24 [d, 6H, J = 6 Hz; (CH3> CH-], 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H, CHsO), 3.93 (dd, 1H, Jax = 6 Hz, Jbx = 7 Hz; H-1), 4.13-4.60 (m, 2H; H-3), 4.95 [sept., IH, 30 J = 6 Hz; (CH3) 2CH], 5.95 ( s, 1 H, J = 4 Hz; H-7), 6.68 (d, 1 H, J = 4 Hz; H-6), 6.70-7.90 ppm (m, 4H; phenyl protons); MS: m / e 327 (M +).

Isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-35 a] -pyrrole-l-carboxylate, mp. 94-95 ° C,

Isopropyl-5-p-isopropoxybenzoyl-l, 2-dihydro-3H-pyrrolo- "[l, 2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, an oil with the following 40 physical constants:

instead of N, N-dimethyl-p-toluamide and registered the course of the reaction by thin layer chromatography. The following connections are obtained:

Isopropyl-5-benzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate, light yellow oil with the following physical constants:

U.V .: 245.311 nm (e 7230, 17800);

I.R.:i).00Cb 1735.1620 cm-1;

NMR: 1.24 [d, 6H, (CHs ^ CH], 2.50-3.13 (m, 2H; H-2); 3.97 (dd, 1H, H-1), 4.18- 4.70 (m, 2H, H-3), 5.00 (sept., IH, (CH3) 2CH), 6.00 (d, 1H, H-7), 6.86 (d, 1H, H -6), 7.10-7.90 ppm (m, 5H, phenyl protons);

M.S .: m / e 297 (M +).

Isopropyl-5-o-toIuoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, an oil with the following physical constants:

U.V .:; CX0H 252.303 nm (e4460, 19100);

I.R .: UmaxCh 1735.1620 cnr1;

NMR: SfSp 1.18, [d, 6H, (CH3) 2CH], 2.28 (s, 3H, o-CHs), 2.50-3.13 (m, 2H, H-2), 3, 92 (dd, 1H, H-1), 4.17-4.70 (m, 2H, H-3), 4.98 [sept. IH, (CHs ^ CH], 5.92 (d, 1H, H-7), 6.43 (d, 1H, H-6), 6.97-7.45 ppm (m, 4H, phenyl protons).

U.V.:\Lx

.CHCli

I.R .: i)

Me0H 251.306 nm (e 5750.16600); 1735.1625 cm-1-

NMR: S? J ^ b 1.22 [d, 6H, (CH3) 2CH], 2.55-3.05 (m, 2H; 45 H-2), 3.97 (dd, 1H, H-1 ), 4.17-4.70 m, 2H, H-3), 4.97 [sept., IH, (CH3) 2CH], [5.93 (d, 2 / 3H), 6.00 (d , 1 / 3H) H-7], [6.42 (d, 2 / 3H), 6.67 (d, 1 / 3H), H-6], 7.07-7.80 ppm (m, 4H ; Phenyl protons).

so isopropyl-5-m-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate, an oil with the following physical constants:

U.V .: ^ aexOH 241.313 nm (s6600.15100);

ss I.R .: u £ "CI '1735,1620,1570 cm-1,

NMR: 1.27 [d, 6H, (CH3) 2CH], 2.50-3.18 (m, 2H, H-2), 3.93 (dd, 1H, H-1), 4.10- 4.63 (m, 2H, H-3), 4.98 [sept., IH, (CH3) 2CH], 5.98 (d, 1H, H-7), 6.67 (d, 1H, H -6), 7.07-7.78 ppm (m, 4H, phenyl protons);

60 M.S .: m / e 331-333 (M +),

Isopropyl-5-p-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, mp. 80.5-81 ° C, isopropyl-5-o-fluorobenzoyl- 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate,

Isopropyl-5-p-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, mp. 72-72.5 ° C, isopropyl-5-m-bromobenzoyl- 1,2-dihy dro-3 H-pyrrolo- [1,2-

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a] pyrrole-l-carboxylate and

Isopropyl-5-p-bromobenzoyl-1,2-dihydro-3 H -pyrrolo- [1,2-a] pyrrole-1-carboxylate.

Production of the starting products

8. A 250 ml three-necked round bottom flask, which contains a magnetic stirrer and is equipped with a drying tube filled with calcium chloride, is charged with 3.36 g of ethanolamine, cooled to 0 to 10 ° C. in an ice bath and added dropwise with stirring with 8.7 g Dimethyl-1,3-acetone-dicarboxylate treated, whereupon methyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) amino-acrylate (III) is obtained spontaneously. When the addition is complete, the ice bath is removed and 80 ml of dry acetonitrile are added to the reaction mixture. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated under reflux for 2 hours. Then the solvent is removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is then evaporated to dryness in vacuo and introduced at the top into a column of 200 g of silica gel in hexane, the column being eluted with a mixture of hexane and ethyl acetate. The fractions eluted with the mixture of hexane and ethyl acetate in a mixing ratio of 1: 1 yield methyl N- (2-hydroxyethyl) -3-carbomethoxy-pyrrole-2-acetate (IV, R = H), which is mixed with that according to Example 1 product obtained is identical.

9. A solution of 6 ml of ethanolamine in 5 ml of water is mixed with 1.74 g of dimethyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and then treated dropwise within 15 minutes while stirring 1.67 ml of 1-bromoacetone, keeping the reaction mixture at a temperature not exceeding 40 ° C. After the addition has ended, the dark reaction mixture is stirred for a further 60 minutes at room temperature and then poured into a mixture of hydrochloric acid and ice, which is saturated with solid sodium chloride, and then extracted three times with 100 ml of ethyl acetate each time. The combined organic extracts are washed neutral with cold water, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue over 30 g of silica gel using a mixture of hexane and ethyl acetate in a mixing ratio of 70:30 as the eluent gives 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methyl-pyrrol-2- acetate, which melts at 78 ° C after recrystallization from a mixture of methylene chloride and hexane and provides the following analytical values:

Analysis for CnHnNOs:

Calculated: C 56.45; H 6.71.

Found: C 56.41; H 6.73.

Similarly, using a stoichiometric equivalent amount of l-bromo-2-butanone, l-bromo-2-pentanone and l-bromo-2-hexanone instead of

1-bromoacetone:

Methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-

2-acetate,

Methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-propyl-pyrrole-2-acetate and

Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate.

10. If you work according to the methods in sections 2,3, 4, 5 and 7, then methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CHî) one after the other in

Methyl N- (2-mesyloxyethyl) -3-carbomethoxy-4-methyl-pyrrole-2-acetate,

Methyl N- (2-iodoethyl) -3-carbomethoxy-4-methyl-pyrrole-2-acetate,

Dimethy 1-1,2-dihy dro-6-methyl-3 H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylate,

1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-l, 7-dicarboxylic acid,

Isopropyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid and

Isopropyl-1,2-dihydro-6-methyl 1-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate (X, R = CH3, R2 = ÌC3H7) transferred.

One works in a similar way using

Methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate,

Methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetate and methyl-N- (2-hydroxy-ethyl) -3 ~ carbomethoxy-4-butylpyrrole-2-acetate instead of methyl-N - (2-hydroxyethyl) -3-carbomethoxy-4-methyl-pyrrole-2-acetate,

so you get that as the end product

Isopropyl-1,2-dihydro-6-ethyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isopropyl-1,2-dihydro-6-propyl-3 H-pyrrolo- [1,2-a] -py rrol-1-carboxylate or

Isopropyl 1,2-dihydro-6-butyl-3 H-pyrrolo- [1,2-a] pyrrole-1 carboxylate.

Example 4

According to the information in Example 1, isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is condensed with N, N-dimethyl-p-toluamide, with Iso -propyl-5-p-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate (XI, R = CHs, R1 = p-CH3, R2 = ÌC3H7).

Using the N, N-dimethylarylamides listed in Example 3 instead of N, N-dimethyl-p-toluamide, the following compounds are obtained in a similar manner:

Isopropyl-5-benzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isopropyl-5-o-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate,

Isopropyl-5-m-toluoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate,

Isopropyl-5-p-ethylbenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

isopropyl-5-o-propylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isopropyl-5-m-butylbenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isopropyl-5-o-methoxybenzoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [l, 2-aj-pyrrole-1-carboxylate, isopropyl-5-p-methoxybenzoyl-1,2-dihydro- 6-methyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate,

Isopropy 1-5 -p-isopropoxybenzoyl-1,2-dihydro-6-methyl 1-3 H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

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Isopropyl-5-o-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate,

Isopropyl-5-m-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isopropyl-5-p-chlorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isopropyl-5-o-fluorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isopropyl-5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [l, 2-a] pyrrole-l-carboxylate, which has the following physical constants:

U.V .: À.max250.315 nm (s 6170.14.100);

I.R .: u ™ CI31734, 1605.1593 cm "1;

NMR: 5? Ss'3l, 25 (d, 6H, J = 6 Hz; ester CHj), 1.83 (s, 3H; RingCH3), 2.49-3.00 (m, 2H; CH2), 3 , 90 (t, IH, SJ = 7.4 Hz; CHCO), 4.10-4.23 (m, 2H; N-CH2), 4.98 (sept., IH, J = 6 Hz; ester CH) , 5.84 (s, 1H, H-3), 7.00 (t, 2H, Jonho = 8.4 Hz, Jhf = 8 Hz; H-3 ', 5'), 7.55 (q, 2H , Jonho = 8.4 Hz, Jhf = 5.5 Hz;

H-2,6 ');

M.S. m / e 1%

329 25 M +

242 100 M + -CChCH (CH3) 2 123 36 F-CsH4CO,

Isopropy 1-5-m-bromobenzoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, and isopropyl-5-p-bromobenzoyl- 1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate.

The end compounds obtained in accordance with section 10 can be converted into the corresponding 5-aroyl-substituted derivatives in a similar manner. Examples include the following:

Isopropy 1-5-benzoyl-1,2-dihy dro-6-ethyl-3 H-pyrrolo- [1,2-a] -py rrol-1-carboxylate,

Isopropyl-5-benzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -py rrol-1-carboxylate,

Isopropyl-5-benzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isopropyl-5-p-toluoyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isopropyl-5-p-ethylbenzoyl-1,2-dihydro-6-propyl-3 H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate,

Isopropyl-5-o-methoxybenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate,

Isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-6-ethyl-3 H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate,

Isopropyl-5-o-chlorobenzoyl-1,2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, isopropyl-5-m-chlorobenzoyl-l, 2- dihydro-6-butyl-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate,

Isopropyl-5-o-flurobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isopropyl-5-p-fluorobenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [l, 2-a] -pyrrol-1-carboxylate, and isopropyl-5-p-bromobenzoyl-1, 2-dihy dro-6-butyl-3 H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate,

Preparation of the starting products 11,710 mg of a 50% suspension of sodium hydride in mineral oil are washed with anhydrous hexane in a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension thus obtained is cooled to -5 ° C. and 4.5 g of methyl N- (2-mesyloxy-methyl) -3-carbomethoxypyrrole-2-acetate are added, the reaction mixture being kept at -5 ° C. for 1 hour to 0 ° C.

The mixture is poured into ice-cooled sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The solid residue is crystallized from ether to give dimethyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylate (VII, R = H), that is identical to the product obtained according to Example 4.

12. A 250 ml three-necked round bottom flask, which is equipped with an inlet and outlet nozzle suitable for dry nitrogen, a magnetic stirring rod and a funnel with pressure compensation, which contains 10.08 g of ethanol, is added dropwise with stirring with 26.1 g of dimethyl 1,3-acetone dicarboxylate charged within 30 minutes, keeping the temperature below 30 ° C. The methyl-3-carbomethoxymethyl-3- (2'-hydro-xyethyl) aminoacrylate (III) formed is mixed with 20 ml of acetonitrile and chloroacetaldehyde, which was previously heated by heating a mixture of 27.4 g of chloroacetaldehyde diethyl acetal with 46.8 g of oxalic acid dihydrate was obtained at 150 to 160 ° C, added within 2 minutes with stirring. The reaction mixture is then heated to boiling under reflux for 5 to 10 minutes, after which the reaction can be regarded as complete, as can be determined by thin layer chromatography analysis using a mixture of acetone and chloroform (mixing ratio 10:90) as eluent. The solvent is then removed under reduced pressure and the residue is mixed with 250 ml of benzene and 250 ml of heptane and then distilled under reduced pressure. The oily residue obtained after distillation is suspended in 50 ml of methylene chloride and 20 g of silica gel are added to the suspension. The methylene chloride mixture is poured into a column containing 200 g of silica gel and, as the eluent, a mixture of ethyl acetate (mixing ratio 20:80). The column is first eluted with 6 liters of a mixture of ethyl acetate and hexane (mixing ratio 20:80) and then with 4 liters of a mixture of ethyl acetate and hexane (50:50). The fractions eluted with the mixture of ethyl acetate and hexane in a mixing ratio of 50:50 are combined and concentrated to give 12.8 g of an oil which is triturated with 20 ml of petroleum ether (30 ° C. to 60 ° C.). The solvent is then evaporated off under reduced pressure. In this way, 11.89 g (32.9% of theory) of methyl N- (2'-hydroxyethyl) -3-carbo-methoxypyrrole-2-acetate (IV, R = H) of melting point 51 to 54 ° C. It is the same product as that obtained in Section 1.

Biodata

A. Testing for analgesic effects in the mouse

Carrying out the test: The compound to be tested is administered orally in an aqueous carrier by means of a gastric tube weighing 18 to 20 g, male Swiss-Webster mice. After 20 minutes, 0.25 ml of a 0.02% solution of phenylquinone is injected intraperitoneally. The solution causes torso twists or convulsions. The animals are observed for their contortions and twists during the next 10 minutes.

Final phase: total number of mice that squirm and average number of twists per mouse.

B. Examination for acute toxicity by os (mouse)

Mode of implementation: The compound to be tested is in an aqueous containing carboxymethyl cellulose

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Suspended carrier. The concentration is adjusted so that the dose can be administered in volumes of 10 ml / kg body weight. Five groups of 6 male Swiss-Webster mice each are tested. The mice are given a single dose with the gastric tube. The fifth group of mice is used as a control group. After administration, the mice are observed for 3 weeks.

Claims (11)

641458 1 R ' where R1 has the above meaning condensed. 2. The method according to claim 1, characterized in that one carries out the condensation in the presence of phosphorus oxychloride. 2nd PATENT CLAIMS 1. Process for the preparation of (d, l) - or (l) -5-aroyl-1,2-dihydro-3 H-pyrrolo [l, 2-a] pyrrole-1-carboxylic acid esters of the formula: COO.R wherein R is the hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R1 is the hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms, the chlorine, fluorine or bromine atom and R2 is an alkyl radical with 1 to 4 carbon atoms mean, wherein the substituent R1 is in the ortho, meta or para position of the aroyl group, characterized in that a compound of the formula: COOR wherein R and R2 have the above meanings, with an amide of the formula: 3. The method according to claim 1, characterized in that the amide used is N, N-dimethylbenzamide. 4. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-o-toluamide. 5. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-m-toluamide. 6. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-p-toluamide. 7. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-p-methoxy-benzamide. 8. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-o-chloro-benzamide. 9. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-m-chlorobenzamide. 10. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-p-chloro-benzamide. 11. The method according to claim 1, characterized in that the amide used is N, N-dimethyl-p-fluorobenzamide.